Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
  • A61K9/0017—Non-human animal skin, e.g. pour-on, spot-on
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/10—Anthelmintics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/14—Ectoparasiticides, e.g. scabicides

Definitions

• the invention relates to a stabilized veterinary composition
• a stabilized veterinary composition comprising Moxidectin in combination with Imidacloprid and an amine base for cutaneous topical application (spot-on), to the use of an amine base for stabilizing Moxidectin, and to the use of an amine base for producing a veterinary composition with improved Moxidectin stability.
• WO 96/17520 relates to compositions for the dermal control of parasitic insects on animals, containing agonists or antagonists of the nicotinergic acetylcholine receptors of insects, solvents from the group benzyl alcohol or optionally substituted pyrrolidones, solvents from the group of cyclic carbonates or lactones and optionally further auxiliaries.
• WO 98/27817 relates to the use of avermectin B1a /B1b, 22,23-dihydroavermectin B1a /B1b, doramectin or moxidectin with imidacloprid, Ti 435 or AKD 1022; optionally further active ingredients and diluents or carriers, for the preparation of compositions for dermal application for combatting of ecto- and endoparasites in a single treatment.
• WO 99/41986 discloses water-containing formulations for the dermal control of parasitic insects on animals containing imidacloprid, 2.5 to 15% by weight of water, solvents from the group alcohols or optionally substituted pyrrolidones, solvents from the group of the cyclic carbonates or lactones, if desired, further auxiliaries and further active compounds.
• US 2002/177597 discloses a synergistic insecticidal composition
• a neuronal sodium channel antagonist in combination with one or more compounds selected from the group consisting of pyrethroids, pyrethroid-type compounds, recombinant nucleopolyhedroviruses capable of expressing an insect toxin, organophosphates, carbamates, formamidines, macrocyclic lactones, amidinohydrazones, GABA antagonists and acetylcholine receptor ligands.
• US 2003/166688 relates to spot-on compositions for the treatment or prophylaxis of parasite infestations in mammals or birds which comprise: (1) a composition comprising (A) an effective amount of a 1-phenylpyrazole derivative; and (B) an effective amount of Emamectin; (2) an acceptable liquid carrier vehicle; and (3) optionally, a crystallization inhibitor.
• WO 2005/074912 provides an antiparasitic composition comprising an anti-parasitically effective amount of an organic amine salt of Closantel, optionally a macrocyclic lactone and a non-irritating solvent system consisting essentially of an alcohol and a glycol derivative. The document is silent on Imidacloprid.
• WO 2006/050816 relates to the use of macrocyclic lactones for treating demodicosis.
• the example 7 (100 mg/25 mg/ml) and example 8 (100 mg/10 mg/ml) correspond to the marketed reference product Advocate® spot-on solution.
• US 2009/0036458 relates to a composition which comprises: an effective amount of (a) Praziquantel and (b) a second endoparasiticidal agent selected from the group consisting of a macrocyclic lactone, Imidacloprid and a combination thereof; and (c) 4-allyl-2-methoxyphenol as carrier.
• US 2011/0160218 relates to formulations which may comprise macrocyclic lactones and at least one spirodioxepinoindole derivative or a spirooxepinoindole derivative for combating parasites in birds and mammals.
• US 2012/071484 relates to a topical parasiticide composition
• a topical parasiticide composition comprising: (i) a phenyl pyrazole insecticide; and/or a neonicotinoid; (ii) a macrocylic lactone and/or an aminoacetonitrile derivatives; (iii) an Insect Growth Regulator; and (iv) a 2-acyl-4-oxo-1,2,3,6,7,11b-4H-pyrazino[2,1a]isoquinoline derivative.
• exemplified formulations contain Moxidectin, Imidacloprid and as a solvent 2-pyrrolidone (lactam, pK A >10.00)
• the document is silent on amine bases, let alone any stabilizing effect thereof.
• CN 106 511 267 provides compound Moxidectin drops as well as a preparation method and application thereof.
• the compound Moxidectin drops have the advantages that Moxidectin and ingredients with insecticidal effect, such as imidacloprid, are compounded and used, so that the drops have good insecticidal effect; meanwhile, in the drops, propylene glycol, moringa seed oil and eucalyptus oil are taken as transdermal agents, wherein the moringa seed oil and the eucalyptus oil are natural plant essential oil with fragrance and can cover up peculiar smell in the drops and improve sense of a user; and further the drops can be used for killing endoparasite and ectoparasite of animals due to good insecticidal effect. While exemplified formulations contain Moxidectin, Imidacloprid and as a solvent 2-pyrrolidone (lactam, pK A >10.00), the document is silent on amine bases, let alone any stabilizing
• US 2013/0225516 relates to stable, highly-effective topical formulations comprising Permethrin, Fipronil and a solvent system that is sufficient to solubilize these two active ingredients and limit degradation of Fipronil to its sulfone, and their uses in topical applications on animals and the environment.
• WO 2014/169092 is directed to stabilized compositions comprising at least one macrocyclic lactone, or derivative thereof, in combination with levamisole, and an amino sugar stabilizing agent, optionally an additional antiparasitic agent, and a method for treating or controlling a parasitic infection or infestation in an animal by administering said composition.
• the document is silent on Imidacloprid.
• An exemplified composition containing Moxidectin and 0.025 %w/w meglumine after storage 12 weeks at 40°C only contains 92.0 %w/w of the originally contained amount of Moxidectin prior to storage, i.e. storage leads to a Moxidectin degradation by 8.0 %w/w.
• US 2019/70158 relates to a monodose veterinary composition for topical application (spot-on) for canines, the said composition comprising: (a) Imidacloprid, between 8.18 and 10.00 %, (b) Moxidectin, between 2.86 and 3.50%, (c) Praziquantel, between 8.18 and 10.00%, and (d) an aprotic solvent selected from dimethyl sulfoxide (DMSO), N,N-dimethylacetamide (DMAC), N,N-dimethylformamide (DMF) and their mixtures, between 65.45 and 80.00 %; together with excipients acceptable from the veterinary viewpoint, where the percentages are related to the composition's total weight.
• DMSO dimethyl sulfoxide
• DMAC N,N-dimethylacetamide
• DMF N,N-dimethylformamide
• WO 2019/101971 relates to a veterinary or pharmaceutical composition
• a veterinary or pharmaceutical composition comprising: (i) about 1-65 % w/v of a pyrethroid or a salt thereof, (ii) a macrocyclic lactone or a salt thereof, (iii) at least one alkalizing agent, (iv) at least one non aqueous solvent, wherein the pH of the composition is comprised between about 6.5 and 8.5, when measured by adding 25% of water to an aliquot of said composition.
• the amount of alkalizing agent preferably sodium hydroxide, depends on the permethrin final grade, permethrin purity grade and permethrin acidity. The document is silent on Imidacloprid.
• Imidacloprid and Moxidectin are both well-established antiparasiticides with proven efficacy.
• Veterinary compositions comprising both Imidacloprid and Moxidectin are difficult to formulate, as the desired routes of administration are different (Moxidectin transdermally/systemically; Imidacloprid intradermally/locally).
• a veterinary composition comprising a combination of Imidacloprid and Moxidectin for spot-on application is commercially available (Advocate®, Bayer Animal Health). This combination is an endectocide, i.e. is effective against both, ecto- and endoparasites, like fleas, lice, mites and different types of worms (see e.g. C. Le Sueur et al., Parasitol Res. 2010 Nov;107(6):1463-9. doi: 10.1007/ s00436-010-2022-8 ; R.D. Paran et al., Vet Med Int. 2011;2011:482746. doi: 10.4061/2011/482746 ; F.
• Moxidectin penetrates through the skin, enters the bloodstream, and distributes in all organs. It acts systemically, targeting endo-parasites and mites. Imidacloprid spreads in the water resistant lipid layer of the skin's surface and acts topically, targeting ectoparasites.
• the commercial product is monthly applied spot-on building up a plateau of antiparasitic Moxidectin for continuous and long-lasting protection against internal parasites.
• the product is waterproof, i.e. remains effective even if the animal becomes wet.
• Advocate® is marketed in polypropylene unit dose pipettes with screw cap. The indicated shelf-life of the commercial product as packaged for sale is 3 years.
• veterinary compositions comprising Moxidectin in combination with Imidacloprid that have improved storage stability so that no specific storage conditions need to be met and need to be mentioned in the product information, respectively.
• the veterinary compositions should ensure that Moxidectin penetrates through the skin, enters the bloodstream, and distributes in all organs, i.e. acts systemically, targeting endo-parasites and mites; whereas Imidacloprid spreads in the water resistant lipid layer of the skin's surface and acts topically, targeting ectoparasites.
• the veterinary compositions should have excellent storage stability and at the same time should provide the desired antiparasitic effect against both, ecto- and endoparasites based upon the desired route of administration (Moxidectin transdermally/systemically; Imidacloprid intradermally/locally).
• the veterinary compositions should be more stable and contain less degradation products/impurities than the already marketed originator product Advocate®.
• Moxidectin is prone to degradation.
• Two degradation products of Moxidectin have been evaluated in finished drug product, the isomer of Moxidectin that is formed due to oxidation of Moxidectin, and 23-keto-nemadectin, a hydrolytic degradation product. It has been surprisingly found that Moxidectin can be stabilized against decomposition into these degradation products by means of an amine base at comparatively low concentrations.
• Imidacloprid is compatible with such amine base. Still further, it has been found that the presence of amine base does not significantly alter the two different desired routes of administration (Moxidectin transdermally/systemically; Imidacloprid intradermally/locally).
• the veterinary composition according to the invention does not require any special temperature storage conditions (according to EMEA/CVMP/422/99/Rev.3 (December 2007): Guideline on Declaration of Storage Conditions in the Product Information of the Pharmaceutical veterinary Medicinal Products and for Active Substance ), whereas the marketed originator product Advocate® according to the currently valid summary of product characteristics (SmPC) should not be stored above 30 °C.
• certain amine bases especially comparatively weak amine bases having pK A values of the corresponding protonated forms (conjugate acids) within the range of from about 7.2 to about 10.0, are capable of stabilizing Moxidectin against chemical decomposition in veterinary compositions additionally containing Imidacloprid.
• a first aspect of the invention relates to a veterinary composition for cutaneous topical application comprising
• composition according to the invention is a veterinary composition that is suitable and typically also devoted for the prevention and/or the treatment of parasitic infections, particularly mixed parasitic infections, in animals, preferably in pets, more preferably in mammalian pets, most preferably in dogs, cats and ferrets.
• the veterinary composition according to the invention is suitable and typically also devoted for cutaneous topical application, preferably as a spot-on composition, more preferably as a spot-on solution.
• a spot-on composition is a dosage form that is to be applied to the skin of the animal.
• the spot-on composition is liquid and is provided e.g. in single-use pipettes or other dispensing devices containing a defined volume of the veterinary composition and containing the entire dose to be administered all at once.
• the spot-on composition is to be applied, e.g. pipetted, to a single spot of skin or to several spots of skin, typically to 1, 2, 3 or 4 spots. Whenever possible, the skin should be undamaged skin of the animal.
• the tip of the pipette When being provided in a pipette, the tip of the pipette may be tipped on the skin of the animal and may be squeezed firmly several times to empty its content directly onto the skin, i.e. to a single spot or to several spots.
• the veterinary composition according to the invention comprises Moxidectin or a physiologically acceptable salt thereof.
• Moxidectin, 23-(O-methyloxime)-F28249 alpha (CAS 113507-06-5, ATCvet code QP54AB02) is a second-generation macrocyclic lactone of the milbemycin family. It is a parasiticide which is active against many internal and external parasites. Moxidectin is active against larval stages (L3, L4) of Dirofilaria immitis. It is also active against gastrointestinal nematodes. Moxidectin interacts with GABA and glutamate-gated chloride channels. This leads to opening of the chloride channels on the postsynaptic junction, the inflow of chloride ions and induction of an irreversible resting state.
• Moxidectin is a semisynthetic derivative of nemadectin which can be produced by fermentation by Streptomyces cyanogriseus subsp.noncyanogenus.
• Moxidectin is: (2aE,2'R,4E,4'E,5'S,6R,6'S,8E,11R,15S,17aR,20R 20aR,20bS)-6'-[(1E)-1,3-Dimethylbut-1-enyl]-20,20b-dihydroxy-4'-(methoxyimino)-5',6,8,19-tetramethyl-3',4',5',6,6',7,10,11,14,15,17a,20,20a,20b-tetradecahydrospiro[2H,17H-11,15-methanofuro-[4,3,2-pq]-[2,6]benzodioxacyclooctadecine-13,2'-pyran]-17-one ((6R,23E,25S)-5O-demethyl-28-deoxy-25-[(1E)-1,3-dimethylbut-1-enyl]-6,28
• Moxidectin is described in e.g. US 4,916,154 . It has the molecular formula C 37 H 53 NO 8 and a molecular weight Mr of 640 g/mol. The structure of Moxidectin is depicted here below:
• Moxidectin is present in a non-salt form.
• Moxidectin upon preparation of the veterinary composition according to the invention, Moxidectin is employed in its non-salt form, whereas it is contemplated that depending upon the chemical environment of the veterinary composition that is influenced by all its excipients, one or more salts of Moxidectin may be formed in situ.
• all quantities and percentages of Moxidectin are expressed in mg and percent by weight, respectively, and refer to the molecular weight of the non-salt form of Moxidectin. Thus, any potential contributions of salt forming entities are not to be considered when determining quantities and percentages.
• the veterinary composition according to the invention is a liquid and contains at least 4.0 mg/ml of Moxidectin, preferably in its non-salt form, more preferably at least 5.0 mg/ml, still more preferably at least 6.0 mg/ml, yet more preferably at least 7.0 mg/ml, even more preferably at least 8.0 mg/ml, most preferably at least 9.0 mg/ml, and in particular at least 10.0 mg/ml, in each case relative to the total volume of the veterinary composition.
• the veterinary composition according to the invention is a liquid and contains at least 12 mg/ml of Moxidectin, preferably in its non-salt form, more preferably at least 15 mg/ml, still more preferably at least 17 mg/ml, yet more preferably at least 19 mg/ml, even more preferably at least 21 mg/ml, most preferably at least 23 mg/ml, and in particular at least 25 mg/ml, in each case relative to the total volume of the veterinary composition.
• the veterinary composition according to the invention is a liquid and contains at most 25 mg/ml of Moxidectin, preferably in its non-salt form, more preferably at most 20 mg/ml, still more preferably at most 18 mg/ml, yet more preferably at most 16 mg/ml, even more preferably at most 14 mg/ml, most preferably at most 12 mg/ml, and in particular at most 10 mg/ml, in each case relative to the total volume of the veterinary composition.
• the veterinary composition according to the invention is a liquid and contains at most 37 mg/ml of Moxidectin, preferably in its non-salt form, more preferably at most 35 mg/ml, still more preferably at most 33 mg/ml, yet more preferably at most 31 mg/ml, even more preferably at most 29 mg/ml, most preferably at most 27 mg/ml, and in particular at most 25 mg/ml, in each case relative to the total volume of the veterinary composition.
• the veterinary composition according to the invention is a liquid and the content of Moxidectin, preferably in its non-salt form, is within the range of 17.5 ⁇ 17.0 mg/ml of, more preferably of 17.5 ⁇ 16.0 mg/ml, still more preferably of 17.5 ⁇ 15.0 mg/ml, yet more preferably of 17.5 ⁇ 14.0 mg/ml, even more preferably of 17.5 ⁇ 12.0 mg/ml, most preferably of 17.5 ⁇ 10.0 mg/ml, and in particular of 17.5 ⁇ 8.0 mg/ml, in each case relative to the total volume of the veterinary composition.
• the veterinary composition according to the invention is a liquid and the content of Moxidectin, preferably in its non-salt form, is within the range of 10 ⁇ 7 mg/ml of, more preferably of 10 ⁇ 6 mg/ml, still more preferably of 10 ⁇ 5 mg/ml, yet more preferably of 10 ⁇ 4 mg/ml, even more preferably of 10 ⁇ 3 mg/ml, most preferably of 10 ⁇ 2 mg/ml, and in particular of 10 ⁇ 1 mg/ml, in each case relative to the total volume of the veterinary composition.
• the veterinary composition according to the invention is a liquid and the content of Moxidectin, preferably in its non-salt form, is within the range of 25 ⁇ 14 mg/ml of, more preferably of 25 ⁇ 12 mg/ml, still more preferably of 25 ⁇ 10 mg/ml, yet more preferably of 25 ⁇ 8 mg/ml, even more preferably of 25 ⁇ 6 mg/ml, most preferably of 25 ⁇ 4 mg/ml, and in particular of 25 ⁇ 2 mg/ml, in each case relative to the total volume of the veterinary composition.
• the veterinary composition according to the invention comprises Imidacloprid or a physiologically acceptable salt thereof.
• Imidacloprid 1-(6-Chloro-3-pyridylmethyl)-N-nitro-imidazolidin-2-ylideneamine (CAS 138261-41-3, ATCvet code QP53AX17) is an ectoparasiticide belonging to the chloronicotinyl group of compounds. Chemically, it is more accurately described as a chloronicotinyl nitroguanidine. Imidacloprid is effective against larval flea stages and adult fleas. Flea larvae in the pet's surroundings are killed after contact with a pet treated with the product.
• Imidacloprid has a high affinity for the nicotinergic acetylcholine receptors in the post-synaptic region of the central nervous system (CNS) of the flea.
• CNS central nervous system
• the ensuing inhibition of cholinergic transmission in insects results in paralysis and death. Due to the weak nature of the interaction with mammalian nicotinergic receptors and the postulated poor penetration through the blood-brain barrier in mammals, it has virtually no effect on the mammalian CNS.
• Imidacloprid has minimal pharmacological activity in mammals.
• Imidacloprid N-(1-((6-chloropyridin-3-yl)methyl)imidazolidin-2-ylidene)nitramide.
• Imidacloprid is described in e.g. US 4,742,060 . It has the chemical formula C 9 H 10 ClN 5 O 2 and a molecular weight Mr of 255.66 g/mol.
• the structure of Imidacloprid is depicted here below:
• Imidacloprid is present in a non-salt form.
• Imidacloprid upon preparation of the veterinary composition according to the invention, Imidacloprid is employed in its non-salt form, whereas it is contemplated that depending upon the chemical environment of the veterinary composition that is influenced by all its excipients, one or more salts of Imidacloprid may be formed in situ.
• all quantities and percentages of Imidacloprid are expressed in mg and percent by weight, respectively, and refer to the molecular weight of the non-salt form of Imidacloprid. Thus, any potential contributions of salt forming entities are not to be considered when determining quantities and percentages.
• the veterinary composition according to the invention is a liquid and contains at least 50 mg/ml of Imidacloprid, preferably in its non-salt form, more preferably at least 60 mg/ml, still more preferably at least 70 mg/ml, yet more preferably at least 80 mg/ml, even more preferably at least 90 mg/ml, most preferably at least 95 mg/ml, and in particular at least 100 mg/ml, in each case relative to the total volume of the veterinary composition.
• the veterinary composition according to the invention is a liquid and contains at most 150 mg/ml of Imidacloprid, preferably in its non-salt form, more preferably at most 140 mg/ml, still more preferably at most 130 mg/ml, yet more preferably at most 120 mg/ml, even more preferably at most 110 mg/ml, most preferably at most 105 mg/ml, and in particular at most 100 mg/ml, in each case relative to the total volume of the veterinary composition.
• the veterinary composition according to the invention is a liquid and the content of Imidacloprid, preferably in its non-salt form, is within the range of 100 ⁇ 70 mg/ml of, more preferably of 100 ⁇ 60 mg/ml, still more preferably of 100 ⁇ 50 mg/ml, yet more preferably of 100 ⁇ 40 mg/ml, even more preferably of 100 ⁇ 30 mg/ml, most preferably of 100 ⁇ 20 mg/ml, and in particular of 100 ⁇ 10 mg/ml, in each case relative to the total volume of the veterinary composition.
• veterinary composition according to the invention may principally contain additional antiparasitic substances, such as Permethrin, Praziquantel, or Fipronil, it is preferred that Moxidectin and Imidacloprid (and optionally benzyl alcohol) are the only antiparasitic substances that are contained in the veterinary composition.
• the veterinary composition according to the invention contains neither Permethrin nor a salt thereof, preferably no pyrethroid at all.
• the veterinary composition according to the invention contains neither Closantel (Clozantel) nor a salt thereof.
• the veterinary composition according to the invention contains neither Levamisole nor a salt thereof.
• the veterinary composition according to the invention contains neither Praziquantel nor a salt thereof.
• the veterinary composition according to the invention preferably belongs to the pharmacotherapeutic group of antiparasitic products, insecticides and repellents, macrocyclic lactones, milbemycins.
• Moxidectin After topical administration of the veterinary composition, i.e. after topical application to the skin of the animal to be treated, Moxidectin is absorbed through the skin, reaching maximum plasma concentrations preferably about 1 to 2 days after treatment in cats and preferably about 4 to 9 days after treatment in dogs. Following absorption from the skin, Moxidectin is distributed systemically and is slowly eliminated from the plasma.
• the veterinary composition additionally contains Imidacloprid, which is rapidly distributed over the animal's skin, typically within one day of application.
• the veterinary composition according to the invention is for topical cutaneous application, preferably as spot-on composition
• the pharmacologically active ingredients Moxidectin and Imidacloprid are administered via different routes.
• Moxidectin is preferably administered transdermally in order to act systemically
• Imidacloprid is preferably administered intradermally in order to act locally within the skin.
• the veterinary composition according to the invention comprises Moxidectin and Imidacloprid, whereas the relative weight ratio of Imidacloprid to Moxidectin is within the range of from 100:1 to 100:60, more preferably 100:2 to 100:55, still more preferably 100:3 to 100:50, yet more preferably 100:4 to 100:45 , even more preferably 100:5 to 100:40, most preferably 100:6 to 100:35, and in particular 100:7 to 100:30.
• the relative weight ratio of Imidacloprid to Moxidectin is within the range of from 100:3 to 100:17, more preferably 100:4 to 100:16, still more preferably 100:5 to 100:15, yet more preferably 100:6 to 100:14 , even more preferably 100:7 to 100:13, most preferably 100:8 to 100:12, and in particular 100:9 to 100:11.
• the relative weight ratio of Imidacloprid to Moxidectin is within the range of from 100:18 to 100:32, more preferably 100:19 to 100:31, still more preferably 100:20 to 100:30, yet more preferably 100:21 to 100:29 , even more preferably 100:22 to 100:28, most preferably 100:23 to 100:27, and in particular 100:24 to 100:26.
• the veterinary composition according to the invention comprises a physiologically acceptable amine base of formula (I) NR 1 R 2 R 3 (I)
• R 1 , R 2 and R 3 are not -H, and more preferably R 1 , R 2 and R 3 are not -H.
• the amine base according to the invention upon preparation of the veterinary composition according to the invention, is employed in its non-salt form, whereas it is contemplated that depending upon the chemical environment of the veterinary composition that is influenced by all its excipients, one or more salts of the amine base according to the invention may be formed in situ.
• all quantities and percentages of the amine base according to the invention are expressed in mg and percent by weight, respectively, and refer to the molecular weight of the non-salt form of the amine base according to the invention. Thus, any potential contributions of salt forming entities are not to be considered when determining quantities and percentages.
• the amine base according to the invention may be a primary amine, secondary amine or tertiary amine.
• the amine base according to the invention is selected from aliphatic primary amines, aliphatic secondary amines and aliphatic tertiary amines.
• the aliphatic residues may be linear or branched, saturated or unsaturated. It is also contemplated that the aliphatic residues are cyclic or that two aliphatic residues together form a ring such that the amino group is part of the ring.
• the amine base according to the invention has a stabilizing effect and thus prevents Moxidectin from chemical decomposition upon storage.
• the amine base according to the invention improves storage stability of the veterinary composition according to the invention such that it does not require storage at temperatures up to 30°C.
• the amine base according to the invention is a comparatively weak base.
• the protonated form of the amine base (conjugate acid) has a pK A value within the range of from 7.20 to 10.00, more preferably from 7.20 to 9.50, still more preferably from 7.20 to 9.00, yet more preferably from 7.20 to 8.50.
• the amine base according to the invention has a pK A value within the range of 7.76 ⁇ 0.55, more preferably 7.76 ⁇ 0.50, still more preferably 7.76 ⁇ 0.45, yet more preferably 7.76 ⁇ 0.40, even more preferably 7.76 ⁇ 0.35, most preferably 7.76 ⁇ 0.25, and in particular 7.76 ⁇ 0.20.
• Preferred amine bases according to the invention and the respective pK A values of their conjugate acids are N-methylmorpholine (pK A 7.38), triethanolamine (pK A 7.76), morpholine (pK A 8.49), N-methyldiethanolamine (pK A 8.52), N-ethyldiethanolamine (pK A 8.7), diethanolamine (pK A 8.88), 1-dimethylamino-2-dimethylaminoethoxyethane (pK A 8.9), tetramethylethylenediamine (pKA 8.97), N,N-dimethyl-ethanolamine (pK A 9.23), monoethanolamine (pK A 9.40), N,N-diethylethanolamine (pK A 9.76), piperazine (pK A 9.8), and 2-methylaminoethanol (pK A 9.95).
• the pK A values are preferably to be determined in water at 23°C.
• the amine base according to the invention is of formula (I) NR 1 R 2 R 3 (I)
• R 1 , R 2 and R 3 independently of one another mean -C 1-6 -alkyl, or -C 1-6 -alkyl-OH; preferably -C 2-6 -alkyl-OH.
• R 1 , R 2 and R 3 independently of one another mean -C 1-3 -alkyl, or -C 1-3 -alkyl-OH; preferably -C 2-3 -alkyl-OH.
• Preferred examples of -C 1-16 -alkyl, -C 1-12 -alkyl, -C 1-6 -alkyl, -C 1-3 -alkyl include but are not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , and -CH(CH 3 ) 2 .
• Preferred examples of -C 1-16 -alkyl-OH, -C 2-16 -alkyl-OH, -C 1-12 -alkyl-OH, -C 2-12 -alkyl-OH, -C 1-6 -alkyl-OH, -C 2-6 -alkyl-OH, -C 1-3 -alkyl-OH, and -C 2-3 -alkyl-OH include but are not limited to -CH 2 CH 2 -OH, -CH(OH)CH 3 , -CH 2 CH 2 CH 2 -OH, -CH(OH)CH 2 CH 3 , and -CH 2 CH(OH)CH 3 .
• the amine base according to the invention is selected from the group consisting of triethanolamine, diethanolamine, monoethanolamine, N-methyldiethanolamine, N-ethyldiethanolamine, N,N-dimethylethanolamine, and N,N-diethylethanolamine.
• Triethanolamine is a particularly preferred amine base according to the invention.
• the concentration of the amine base according to the invention in the veterinary composition according to the invention is not particularly limited.
• the concentration of the amine base according to the invention is adjusted such that it provides the desired stabilizing effect to Moxidectin but does not significantly exceed to concentration that is needed for this purpose. This concentration may depend upon various factors including the concentration of Moxidectin and can be easily determined for every amine base according to the invention by simple routine testing.
• the weight content of the amine base according to the invention preferably triethanolamine, diethanolamine, monoethanolamine, N-methyldiethanolamine, N-ethyldiethanolamine, N,N-dimethylethanolamine, or N,N-diethylethanolamine, more preferably triethanolamine, is within the range of from 1 ppm to 1000 ppm, relative to the total weight of the veterinary composition.
• ppm shall be based on weight, i.e. "ppmw”.
• the weight content of the amine base according to the invention is at least 40 ppm, more preferably at least 50 ppm, still more preferably at least 60 ppm, yet more preferably at least 70 ppm, even more preferably at least 80 ppm, most preferably at least 90 ppm, and in particular at least 100 ppm, relative to the total weight of the veterinary composition.
• the weight content of the amine base according to the invention is at most 500 ppm, more preferably at most 400 ppm, still more preferably at most 350 ppm, yet more preferably at most 300 ppm, even more preferably at most 250 ppm, most preferably at most 200 ppm, and in particular at most 150 ppm, relative to the total weight of the veterinary composition.
• the weight content of the amine base according to the invention is at most 240 ppm, more preferably at most 230 ppm, still more preferably at most 220 ppm, yet more preferably at most 210 ppm, even more preferably at most 200 ppm, most preferably at most 190 ppm, and in particular at most 180 ppm, relative to the total weight of the veterinary composition.
• the weight content of the amine base according to the invention is within the range of 100 ⁇ 90 ppm, more preferably 100 ⁇ 80 ppm, still more preferably 100 ⁇ 70 ppm, yet more preferably 100 ⁇ 60 ppm, even more preferably 100 ⁇ 50 ppm, most preferably 100 ⁇ 40 ppm, and in particular 100 ⁇ 30 ppm, relative to the total weight of the veterinary composition.
• the veterinary composition according to the invention has a defined pH value that is to be determined under the following conditions: (i) when the veterinary composition is an aqueous composition, its pH value is directly determined on the veterinary composition as such; or (ii) when the veterinary composition is an anhydrous composition, its pH value is determined by mixing the anhydrous veterinary composition with pure water in order to obtain a 1% v/v aqueous dispersion (e.g. water suspension) and determining the resultant pH value on the thus obtained mixture.
• a v/v aqueous dispersion e.g. water suspension
• the following preferred pH values refer to either condition (i) or condition (ii), whereas condition (ii) is preferred according to the invention.
• the pH value of the veterinary composition is at least 5.3, more preferably at least 5.4, still more preferably at least 5.5, yet more preferably at least 5.6, even more preferably at least 5.7, most preferably at least 5.8, and in particular at least 5.9.
• the pH value of the veterinary composition is at most 6.8, more preferably at most 6.7, still more preferably at most 6.6, yet more preferably at most 6.5, even more preferably at most 6.4, most preferably at most 6.3, and in particular at most 6.2.
• the pH value of the veterinary composition is within the range of from 5.7 to 6.4, more preferably from 5.8 to 6.3, still more preferably from 5.9 to 6.2.
• the veterinary composition according to the invention is a liquid, preferably a solution, suspension or emulsion.
• the veterinary composition according to the invention is anhydrous, i.e. contains less than 2 wt.-% water, preferably not more than 1.5 wt.-%, more preferably not more than 1.0 wt.-%, most preferably not more than 0.5 wt.-%, relative to the total weight of the veterinary composition. Solutions are particularly preferred, especially anhydrous solutions.
• the veterinary composition according to the invention has improved storage stability.
• the veterinary composition according to the invention is stable in accordance with EMEA/CVMP/ 422/99/Rev.3 (20 December 2007) Guideline on Declaration of Storage Conditions in the Product Information of the Pharmaceutical veterinary Medicinal Products and for Active Substance under testing conditions 25°C/60% RH (long term), 40°C/75% RH (accelerated).
• the veterinary composition according to the invention may contain conventional excipients in conventional amounts. Suitable excipients and their amounts are known to the skilled person. In this regard it can be referred to e.g. P.J. Sheskey et al., Handbook of Pharmaceutical Excipients, 8th Revised edition (11. August 2017), Pharmaceutical Press .
• the veterinary composition according to the invention additionally contains one or more excipients selected from antioxidants, preservatives, solvents, and co-solvents.
• solvent and "co-solvent".
• a co-solvent is added to a primary solvent in a comparatively small amount to increase the solubility of a poorly-soluble compound, in the present case of Moxidectin and/or Imidacloprid.
• a solvent i.e. a primary solvent
• the amount of the solvent will typically exceed to amount of the co-solvent.
• Suitable antioxidants include but are not limited to antioxidants selected from the group consisting of di-tert-butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), alpha-tocopherol, alpha-tocopheryl acetate, ascorbic acid, salts of ascorbic acid, monothioglycerol, phosphorous acid, coniferyl benzoate, nordihydro-guajaretic acid, gallus acid esters, sodium bisulfite, and mixtures thereof.
• BHT di-tert-butylhydroxytoluene
• BHA butylhydroxyanisole
• alpha-tocopherol alpha-tocopheryl acetate
• ascorbic acid salts of ascorbic acid, monothioglycerol, phosphorous acid, coniferyl benzoate, nordihydro-guajaretic acid, gallus acid esters, sodium bisulfite, and mixtures thereof.
• Butylhydroxytoluene preferably di-ter
• the veterinary composition according to the invention is a liquid and contains at least 0.4 mg/ml of antioxidant, preferably of butylhydroxytoluene, more preferably at least 0.5 mg/ml, still more preferably at least 0.6 mg/ml, yet more preferably at least 0.7 mg/ml, even more preferably at least 0.8 mg/ml, most preferably at least 0.9 mg/ml, and in particular at least 1.0 mg/ml, in each case relative to the total volume of the veterinary composition.
• antioxidant preferably of butylhydroxytoluene
• the veterinary composition according to the invention is a liquid and contains at most 2.2 mg/ml of antioxidant, preferably of butylhydroxytoluene, more preferably at most 2.0 mg/ml, still more preferably at most 1.8 mg/ml, yet more preferably at most 1.6 mg/ml, even more preferably at most 1.4 mg/ml, most preferably at most 1.2 mg/ml, and in particular at most 1.0 mg/ml, in each case relative to the total volume of the veterinary composition.
• antioxidant preferably of butylhydroxytoluene
• the preferably at most 2.0 mg/ml still more preferably at most 1.8 mg/ml
• yet more preferably at most 1.6 mg/ml even more preferably at most 1.4 mg/ml
• most preferably at most 1.2 mg/ml most preferably at most 1.2 mg/ml
• at most 1.0 mg/ml in each case relative to the total volume of the veterinary composition.
• the veterinary composition according to the invention is a liquid and the content of antioxidant, preferably of butylhydroxytoluene, is within the range of 1.0 ⁇ 0.9 mg/ml of, more preferably of 1.0 ⁇ 0.8 mg/ml, still more preferably of 1.0 ⁇ 0.7 mg/ml, yet more preferably of 1.0 ⁇ 0.6 mg/ml, even more preferably of 1.0 ⁇ 0.5 mg/ml, most preferably of 1.0 ⁇ 0.4 mg/ml, and in particular of 1.0 ⁇ 0.3 mg/ml, in each case relative to the total volume of the veterinary composition.
• antioxidant preferably of butylhydroxytoluene
• Suitable solvents include but are not limited to solvents selected from the group consisting of benzyl alcohol, methanol, ethanol, n-propanol, isopropanol, glycerol, acetone, dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMAC), N,N-dimethylformamide (DMF), and mixtures thereof.
• Benzyl alcohol is a particularly preferred solvent according to the invention. According to the ATC index 2019, benzyl alcohol (P03AX06) belongs to the subgroup of other ectoparasiticides, incl. scabicides (P03AX), which belongs to the group of ectoparasiticides, incl.
• scabicides which belongs to the class of ectoparasiticides, incl. scabicides, insecticides and repellents (P03).
• Moxidectin and preferably present Imidacloprid benzyl alcohol also may also contribute to the overall antiparasitic efficacy, potency and efficiency of the veterinary composition according to the invention.
• the veterinary composition according to the invention is a liquid and contains at least 500 mg/ml of solvent, preferably of benzyl alcohol, more preferably at least 550 mg/ml, still more preferably at least 600 mg/ml, yet more preferably at least 650 mg/ml, even more preferably at least 700 mg/ml, most preferably at least 750 mg/ml, and in particular at least 800 mg/ml, in each case relative to the total volume of the veterinary composition.
• the veterinary composition according to the invention is a liquid and contains at most 880 mg/ml of solvent, preferably of benzyl alcohol, more preferably at most 870 mg/ml, still more preferably at most 860 mg/ml, yet more preferably at most 850 mg/ml, even more preferably at most 840 mg/ml, most preferably at most 830 mg/ml, and in particular at most 825 mg/ml, in each case relative to the total volume of the veterinary composition.
• solvent preferably of benzyl alcohol
• solvent preferably at most 870 mg/ml
• still more preferably at most 860 mg/ml yet more preferably at most 850 mg/ml, even more preferably at most 840 mg/ml, most preferably at most 830 mg/ml, and in particular at most 825 mg/ml, in each case relative to the total volume of the veterinary composition.
• the veterinary composition according to the invention is a liquid and the content of solvent, preferably of benzyl alcohol, is within the range of 815 ⁇ 40 mg/ml of, more preferably of 815 ⁇ 35 mg/ml, still more preferably of 815 ⁇ 30 mg/ml, yet more preferably of 815 ⁇ 25 mg/ml, even more preferably of 815 ⁇ 20 mg/ml, most preferably of 815 ⁇ 15 mg/ml, and in particular of 815 ⁇ 10 mg/ml, in each case relative to the total volume of the veterinary composition.
• solvent preferably of benzyl alcohol
• Suitable co-solvents include but are not limited to co-solvents selected from the group consisting of propylene carbonate, ethylene carbonate, 1,2-butylene carbonate, glycerol carbonate, ethylene glycol, propylene glycol, butyl diglycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether, dipropylene glycol n-butyl ether, and mixtures thereof.
• Propylene carbonate is a particularly preferred co-solvent according to the invention.
• the veterinary composition according to the invention is a liquid and contains at least 80 mg/ml of co-solvent, preferably of propylene carbonate, more preferably at least 100 mg/ml, still more preferably at least 120 mg/ml, yet more preferably at least 140 mg/ml, even more preferably at least 160 mg/ml, most preferably at least 165 mg/ml, and in particular at least 800 mg/ml, in each case relative to the total volume of the veterinary composition.
• co-solvent preferably of propylene carbonate
• the veterinary composition according to the invention is a liquid and contains at most 280 mg/ml of co-solvent, preferably of propylene carbonate, more preferably at most 260 mg/ml, still more preferably at most 240 mg/ml, yet more preferably at most 220 mg/ml, even more preferably at most 200 mg/ml, most preferably at most 180 mg/ml, and in particular at most 165 mg/ml, in each case relative to the total volume of the veterinary composition.
• co-solvent preferably of propylene carbonate
• the veterinary composition according to the invention is a liquid and the content of co-solvent, preferably of propylene carbonate, is within the range of 165 ⁇ 70 mg/ml of, more preferably of 165 ⁇ 60 mg/ml, still more preferably of 165 ⁇ 50 mg/ml, yet more preferably of 165 ⁇ 40 mg/ml, even more preferably of 165 ⁇ 30 mg/ml, most preferably of 165 ⁇ 20 mg/ml, and in particular of 165 ⁇ 10 mg/ml, in each case relative to the total volume of the veterinary composition.
• co-solvent preferably of propylene carbonate
• the veterinary composition according to the invention may optionally contain further excipients, such as carriers, diluents, extenders, solubilizers, surfactants, skin permeation enhancers, fragrances, bitter substances, and the like.
• excipients such as carriers, diluents, extenders, solubilizers, surfactants, skin permeation enhancers, fragrances, bitter substances, and the like.
• the veterinary composition according to the invention comprises, preferably essentially consists of
• veterinary composition according to the invention preferably of the veterinary spot-on solution according to the invention, are compiled as embodiments A 1 to A 12 in the table here below: [mg/ml] A 1 A 2 A 3 A 4 Imidacloprid, preferably in its non-salt form 100 ⁇ 90 100 ⁇ 70 100 ⁇ 50 100 ⁇ 30 Moxidectin, preferably in its non-salt form 17.5 ⁇ 15 17.5 ⁇ 13 17.5 ⁇ 10 17.5 ⁇ 8 solvent, preferably benzyl alcohol 825 ⁇ 800 825 ⁇ 600 825 ⁇ 400 825 ⁇ 200 co-solvent, preferably propylene carbonate 165 ⁇ 150 165 ⁇ 120 165 ⁇ 90 165 ⁇ 60 antioxidant, preferably butylhydroxytoluene 1.0 ⁇ 0.9 1.0 ⁇ 0.7 1.0 ⁇ 0.5 1.0 ⁇ 0.3 amine base, preferably triethanolamine 0.10 ⁇ 0.09 0.10 ⁇ 0.07 0.10 ⁇ 0.05 0.10 ⁇ 0.03 [mg/ml] A 5 A 6 A 7 A 8 Imidacloprid,
• the veterinary composition according to the invention comprises, preferably essentially consists of
• the veterinary composition according to the invention comprises, preferably essentially consist of
• the veterinary composition according to the invention comprises, preferably essentially consists of
• the veterinary composition according to the invention comprises, preferably essentially consist of
• the veterinary composition according to the invention is preferably packaged in suitable containers, preferably in unit dose pipettes or other suitable dispensing devices, that are preferably disposable and intended for single use.
• Unit dose pipettes are preferably equipped with a screw cap.
• typical volumes of the veterinary composition in a container may range from e.g. about 0.25 ml to 5.0 ml.
• Preferred containers are unit dose pipettes containing 0.4 ml, or 0.8 ml, or 1.0 ml, or 2.5 ml, or 4.0 ml.
• a multitude of pipettes may then be packaged e.g. in a blister pack containing e.g. 3 or 6 unit dose pipettes.
• Preferred unit dose pipettes contain the following volumes of the veterinary composition according to the invention:
• compositions according to the invention can be manufactured by standard procedures of pharmaceutical technology using standard equipment that is commercially available.
• the veterinary composition is a spot-on solution in solvent and co-solvent additionally containing excipients such as antioxidant
• solvent and co-solvent additionally containing excipients such as antioxidant
• Moxidectin and Imidacloprid it is preferred to firstly mix and dissolve excipients and amine base according to the invention in solvent and co-solvent, and thereafter to add Moxidectin and Imidacloprid.
• the resultant mixture may then be stirred until all ingredients are fully dissolved.
• the resultant solution may then be filtered, e.g. through a stainless steel filter. Aliquots of the solution may be filled into pipettes, e.g. made of polypropylene, which may be sealed and packaged, e.g. in laminated triplex bags (PET/Al/LDPE).
• Another aspect of the invention relates to the veterinary composition according to the invention as described above for use in the treatment or prevention of parasitic infections in pets.
• another aspect of the invention relates to the use of Moxidectin or a physiologically acceptable salt thereof in combination with Imidacloprid or a physiologically acceptable salt thereof, for the manufacture of the veterinary composition according to the invention as described above for the treatment or prevention of parasitic infections in pets.
• another aspect of the invention relates to a method of treating or preventing parasitic infections in pets comprising administering, preferably topically cutaneously, an effective amount of the veterinary composition according to the invention as described above.
• the pets are selected from cats, ferrets and dogs.
• the veterinary composition according to the invention is useful for treating various mixed parasitic infections.
• exemplified mixed parasitic infections that can be treated or prevented with the veterinary composition according to the invention include but are not limited to
• the veterinary composition according to the invention is preferably used as part of a treatment strategy for flea allergy dermatitis (FAD) in cats.
• FAD allergy dermatitis
• exemplified mixed parasitic infections that can be treated or prevented with the veterinary composition according to the invention include but are not limited to
• exemplified mixed parasitic infections that can be treated or prevented with the veterinary composition according to the invention include but are not limited to
• the veterinary composition according to the invention is preferably used as part of a treatment strategy for flea allergy dermatitis (FAD) in dogs.
• the veterinary composition according to the invention is administered topically to the skin, preferably to undamaged skin.
• the veterinary composition according to the invention is administered cutaneously by applying it in form of a spot-on composition, preferably spot-on solution to the skin.
• a spot-on composition preferably spot-on solution
• the spot-on composition is to be applied, e.g. pipetted, to a single spot of skin or to several spots of skin, typically to 1, 2, 3 or 4 spots.
• the recommended minimum dose of Imidacloprid is 10 mg per kg body weight.
• concentration of Imidacloprid in the veterinary solution is e.g. 100 mg/ml, this corresponds to 0.1 ml per kg body weight.
• the recommended minimum dose of Moxidectin then corresponds to the amount of Moxidectin that is contained in this volume of the veterinary composition as calculated for Imidacloprid.
• Imidacloprid and Moxidectin are also compiled in the table here below: mg per kg body weight body weight Imidacloprid Moxidectin Ferrets all minimum 10 minimum 1.0 Cats ⁇ 4 kg minimum 10 minimum 1.0 > 4 to 8 kg 10 to 20 1.0 to 2.0 Dogs ⁇ 4 kg minimum 10 minimum 2.5 > 4 to 10 kg 10 to 25 2.5 to 6.25 > 10 to 25 kg 10 to 25 2.5 to 6.25 > 25 to 40 kg 10 to 16 2.5 to 4.0
• the veterinary composition according to the invention is administered at least once.
• an effective amount of the veterinary composition according to the invention is administered a single time and then treatment is terminated.
• a first effective amount of the veterinary composition according to the invention is administered, i.e. applied to the skin, and after 2 weeks, 3 weeks or 4 weeks, a second effective amount of the veterinary composition according to the invention is administered, i.e. applied to the skin. After administration of the second effective amount, treatment may be terminated.
• treatment may be continued, i.e. after 2 weeks, 3 weeks or 4 weeks, a third effective amount of the veterinary composition according to the invention is administered, i.e. applied to the skin. After administration of the third effective amount, treatment may be terminated or continued.
• every administered subsequent effective amount of the veterinary composition according to the invention preferably essentially corresponds to every administered preceding effective amount of the veterinary composition according to the invention (i.e. first effective dose ⁇ second effective dose ⁇ third effective dose and so on).
• Another aspect of the invention relates to the use of an amine base according to the invention as described above, preferably triethanolamine, diethanolamine, monoethanolamine, N-methyldiethanolamine, N-ethyldiethanolamine, N,N-dimethylethanolamine, or N,N-diethylethanolamine, more preferably triethanolamine, for stabilizing Moxidectin or a physiologically acceptable salt thereof.
• Moxidectin is stabilized against chemical decomposition, preferably in solution.
• Another aspect of the invention relates to the use of an amine base according to the invention as described above, preferably triethanolamine, diethanolamine, monoethanolamine, N-methyldiethanolamine, N-ethyldiethanolamine, N,N-dimethylethanolamine, or N,N-diethylethanolamine, more preferably triethanolamine, for producing a veterinary composition with improved stability of Moxidectin or a physiologically acceptable salt thereof, preferably for producing a veterinary composition according to the invention as described above.
• an amine base according to the invention as described above, preferably triethanolamine, diethanolamine, monoethanolamine, N-methyldiethanolamine, N-ethyldiethanolamine, N,N-dimethylethanolamine, or N,N-diethylethanolamine, more preferably triethanolamine, for producing a veterinary composition with improved stability of Moxidectin or a physiologically acceptable salt thereof, preferably for producing a veterinary composition according to the invention as described above.
• compositions were prepared: Imidacloprid/Moxidectin spot-on solution Example 1
• Example 2 Strength 100 mg/10 m/ml 100 m/25 m/ml Ingredient Quantity/unit [mg/ml] Quantity/unit [mg/ml] Imidacloprid 100.00 100.00 Moxidectin 10.00 25.00 Propylene Carbonate 165.00 165.00 Butylhydroxytoluene 1.00 1.00 Triethanolamine 0.11* 0.11* Benzyl Alcohol 822.19 807.19 0.11 mg/ml of triethanolamine corresponds to 100 ppm of triethanolamine
• the solution is filled into polypropylene pipette. Pipettes are sealed and put into the laminated triplex bags (PET/Al/LDPE).
• Each spot-on solution was filled into polypropylene pipette and the pipettes were stored in aluminum triplex bags under accelerated storage conditions (6 months at 40°C and 75% r.h.).
• compositions according to the invention containing amine base triethanolamine have a significantly improved storage stability compared to commercial Advocate® product not containing amine base.
• Two spot-on solutions A and B were prepared according to Examples 7 and 8 of WO 2006/050816 :
• Example 4B Ingredient Quantity/unit [mg/ml] Quantity/unit [mg/ml] Imidacloprid 100 100 Moxidectin 10 25 Propylene carbonate 165.0 165.0 Butylhydroxytoluene 1 1 Benzyl alcohol 822.3 807.3
• Each spot-on solution was filled into polypropylene pipette and the pipettes were stored in aluminum triplex bags under accelerated storage conditions (3 or 6 months at 40°C and 75% r.h.) and long-term conditions (12 or 24 months at 25°C and 60% r.h.).
• the stability test were additionally performed by preparing inventive formulations containing Moxidectin obtained from different sources I (I-1, 1-2, 1-3 and 1-4) and II (1-5 and 1-6).
• the veterinary compositions according to the invention containing amine base triethanolamine have a significantly improved storage stability compared to compositions disclosed in prior art document not containing amine base.
• the data show that the amount of impurities that formed in the veterinary compositions according to the invention containing amine base triethanolamine is significantly lower than in the compositions disclosed in prior art document not containing amine base.
• the increase in the amount of impurities in the veterinary compositions according to the invention is minimal, whereas in the prior art compositions the amount of impurities that formed already in the first year after subjecting to long term storage conditions significantly increased.

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